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1.
Proc Natl Acad Sci U S A ; 121(5): e2306816121, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38266047

RESUMO

Astrocyte activation is associated with neuropathology and the production of tissue inhibitor of metalloproteinase-1 (TIMP1). TIMP1 is a pleiotropic extracellular protein that functions both as a protease inhibitor and as a growth factor. Astrocytes that lack expression of Timp1 do not support rat oligodendrocyte progenitor cell (rOPC) differentiation, and adult global Timp1 knockout (Timp1KO) mice do not efficiently remyelinate following a demyelinating injury. Here, we performed an unbiased proteomic analysis and identified a fibronectin-derived peptide called Anastellin (Ana) that was unique to the Timp1KO astrocyte secretome. Ana was found to block rOPC differentiation in vitro and enhanced the inhibitory influence of fibronectin on rOPC differentiation. Ana is known to act upon the sphingosine-1-phosphate receptor 1, and we determined that Ana also blocked the pro-myelinating effect of FTY720 (or fingolimod) on rOPC differentiation in vitro. Administration of FTY720 to wild-type C57BL/6 mice during MOG35-55-experimental autoimmune encephalomyelitis ameliorated clinical disability while FTY720 administered to mice lacking expression of Timp1 (Timp1KO) had no effect. Analysis of Timp1 and fibronectin (FN1) transcripts from primary human astrocytes from healthy and multiple sclerosis (MS) donors revealed lower TIMP1 expression was coincident with elevated FN1 in MS astrocytes. Last, analyses of proteomic databases of MS samples identified Ana peptides to be more abundant in the cerebrospinal fluid (CSF) of human MS patients with high disease activity. A role for Ana in MS as a consequence of a lack of astrocytic TIMP-1 production could influence both the efficacy of fingolimod responses and innate remyelination potential in the MS brain.


Assuntos
Esclerose Múltipla , Fragmentos de Peptídeos , Inibidor Tecidual de Metaloproteinase-1 , Animais , Camundongos , Ratos , Astrócitos , Fibronectinas/genética , Cloridrato de Fingolimode/farmacologia , Camundongos Endogâmicos C57BL , Esclerose Múltipla/tratamento farmacológico , Proteômica , Inibidor Tecidual de Metaloproteinase-1/genética
2.
bioRxiv ; 2023 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-37205496

RESUMO

Ischemic stroke results in a loss of tissue homeostasis and integrity, the underlying pathobiology of which stems primarily from the depletion of cellular energy stores and perturbation of available metabolites 1 . Hibernation in thirteen-lined ground squirrels (TLGS), Ictidomys tridecemlineatus , provides a natural model of ischemic tolerance as these mammals undergo prolonged periods of critically low cerebral blood flow without evidence of central nervous system (CNS) damage 2 . Studying the complex interplay of genes and metabolites that unfolds during hibernation may provide novel insights into key regulators of cellular homeostasis during brain ischemia. Herein, we interrogated the molecular profiles of TLGS brains at different time points within the hibernation cycle via RNA sequencing coupled with untargeted metabolomics. We demonstrate that hibernation in TLGS leads to major changes in the expression of genes involved in oxidative phosphorylation and this is correlated with an accumulation of the tricarboxylic acid (TCA) cycle intermediates citrate, cis-aconitate, and α-ketoglutarate-αKG. Integration of the gene expression and metabolomics datasets led to the identification of succinate dehydrogenase (SDH) as the critical enzyme during hibernation, uncovering a break in the TCA cycle at that level. Accordingly, the SDH inhibitor dimethyl malonate (DMM) was able to rescue the effects of hypoxia on human neuronal cells in vitro and in mice subjected to permanent ischemic stroke in vivo . Our findings indicate that studying the regulation of the controlled metabolic depression that occurs in hibernating mammals may lead to novel therapeutic approaches capable of increasing ischemic tolerance in the CNS.

3.
bioRxiv ; 2023 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-36824834

RESUMO

Astrocyte activation is associated with neuropathology and the production of tissue inhibitor of metalloproteinase-1 (TIMP1). TIMP1 is a pleiotropic extracellular protein that functions both as a protease inhibitor and as a growth factor. We have previously demonstrated that murine astrocytes that lack expression of Timp1 do not support rat oligodendrocyte progenitor cell (rOPC) differentiation, and adult global Timp1 knockout ( Timp1 KO ) mice do not efficiently remyelinate following a demyelinating injury. To better understand the basis of this, we performed unbiased proteomic analyses and identified a fibronectin-derived peptide called anastellin that is unique to the murine Timp1 KO astrocyte secretome. Anastellin was found to block rOPC differentiation in vitro and enhanced the inhibitory influence of fibronectin on rOPC differentiation. Anastellin is known to act upon the sphingosine-1-phosphate receptor 1 (S1PR1), and we determined that anastellin also blocked the pro-myelinating effect of FTY720 (or fingolimod) on rOPC differentiation in vitro . Further, administration of FTY720 to wild-type C57BL/6 mice during MOG 35-55 -EAE ameliorated clinical disability while FTY720 administered to mice lacking expression of Timp1 in astrocytes ( Timp1 cKO ) had no effect. Analysis of human TIMP1 and fibronectin ( FN1 ) transcripts from healthy and multiple sclerosis (MS) patient brain samples revealed an inverse relationship where lower TIMP1 expression was coincident with elevated FN1 in MS astrocytes. Lastly, we analyzed proteomic databases of MS samples and identified anastellin peptides to be more abundant in the cerebrospinal fluid (CSF) of human MS patients with high versus low disease activity. The prospective role for anastellin generation in association with myelin lesions as a consequence of a lack of astrocytic TIMP-1 production could influence both the efficacy of fingolimod responses and the innate remyelination potential of the the MS brain. Significance Statement: Astrocytic production of TIMP-1 prevents the protein catabolism of fibronectin. In the absence of TIMP-1, fibronectin is further digested leading to a higher abundance of anastellin peptides that can bind to sphingosine-1-phosphate receptor 1. The binding of anastellin with the sphingosine-1-phosphate receptor 1 impairs the differentiation of oligodendrocytes progenitor cells into myelinating oligodendrocytes in vitro , and negates the astrocyte-mediated therapeutic effects of FTY720 in the EAE model of chronic CNS inflammation. These data indicate that TIMP-1 production by astrocytes is important in coordinating astrocytic functions during inflammation. In the absence of astrocyte produced TIMP-1, elevated expression of anastellin may represent a prospective biomarker for FTY720 therapeutic responsiveness.

4.
Exp Neurol ; 355: 114124, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35644426

RESUMO

Within the adult central nervous system (CNS) of most mammals resides a resident stem cell population, known as neural stem cells (NSCs). NSCs are located within specific niches of the CNS and maintain a self-renewal and proliferative capacity to generate new neurons, astrocytes, and oligodendrocytes throughout adulthood. The NSC niches are dynamic and active environments that are within proximity to the systemic circulation and the cerebrospinal fluid (CSF). Therefore, NSCs respond not only to factors present in the local microenvironment of the niche but also to factors present in the systemic macroenvironment. The factors can be soluble forms such as cytokines and chemokines located in the circulation or directly from local cells, such as microglia and astrocytes. Additionally, recent evidence points towards physiological aging and its association with a progressive loss of function and a decline in the self-renewal and regenerative capacities of CNS NSCs, which can be further exacerbated by changes in the local and systemic milieu. This review will highlight the main intrinsic and extrinsic regulators of neural stem cell function under homeostatic and inflammatory conditions including those trafficked within extracellular membrane vesicles. Further, discussion will center around how intrinsic and extrinsic factors impact normal homeostatic functions within the adult brain and in aging.


Assuntos
Células-Tronco Neurais , Neurogênese , Animais , Encéfalo , Diferenciação Celular , Inflamação/metabolismo , Mamíferos , Células-Tronco Neurais/metabolismo , Neurogênese/fisiologia , Nicho de Células-Tronco/fisiologia
5.
Cell Tissue Res ; 387(3): 399-414, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34820704

RESUMO

Glial scars are a common pathological occurrence in a variety of central nervous system (CNS) diseases and injuries. They are caused after severe damage and consist of reactive glia that form a barrier around the damaged tissue that leads to a non-permissive microenvironment which prevents proper endogenous regeneration. While there are a number of therapies that are able to address some components of disease, there are none that provide regenerative properties. Within the past decade, neural stem cells (NSCs) have been heavily studied due to their potent anti-inflammatory and reparative capabilities in disease and injury. Exogenously applied NSCs have been found to aid in glial scar healing by reducing inflammation and providing cell replacement. However, endogenous NSCs have also been found to contribute to the reactive environment by different means. Further understanding how NSCs can be leveraged to aid in the resolution of the glial scar is imperative in the use of these cells as regenerative therapies. To do so, humanised 3D model systems have been developed to study the development and maintenance of the glial scar. Herein, we explore the current work on endogenous and exogenous NSCs in the glial scar as well as the novel 3D stem cell-based technologies being used to model this pathology in a dish.


Assuntos
Doenças do Sistema Nervoso Central , Células-Tronco Neurais , Traumatismos da Medula Espinal , Cicatriz/patologia , Gliose/patologia , Humanos , Células-Tronco Neurais/patologia , Neuroglia/patologia , Traumatismos da Medula Espinal/terapia
6.
Aging Dis ; 12(6): 1462-1475, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34527422

RESUMO

Astrocytes are an abundant and dynamic glial cell exclusive to the central nervous system (CNS). In the context of injury, inflammation, and/or diseases of the nervous system, astrocyte responses, termed reactive astrogliosis, are a recognized pathological feature across a range of conditions and diseases. However, the impact of reactive astrogliosis is not uniform and varies by context and duration (time). In recent years, extracellular communication between glial cells via extracellular vesicles (EVs) has garnered interest as a process connected with reactive astrogliosis. In this review, we relate recent findings on astrocyte-derived extracellular vesicles (ADEVs) with a focus on factors that can influence the effects of ADEVs and identified age related changes in the function of ADEVs. Additionally, we will discuss the current limitations of existing experimental approaches and identify questions that highlight areas for growth in this field, which will continue to enhance our understanding of ADEVs in age-associated processes.

7.
Front Immunol ; 12: 705920, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34249016

RESUMO

Compelling evidence exists that patients with chronic neurological conditions, which includes progressive multiple sclerosis, display pathological changes in neural metabolism and mitochondrial function. However, it is unknown if a similar degree of metabolic dysfunction occurs also in non-neural cells in the central nervous system. Specifically, it remains to be clarified (i) the full extent of metabolic changes in tissue-resident microglia and infiltrating macrophages after prolonged neuroinflammation (e.g., at the level of chronic active lesions), and (ii) whether these alterations underlie a unique pathogenic phenotype that is amenable for therapeutic targeting. Herein, we discuss how cell metabolism and mitochondrial function govern the function of chronic active microglia and macrophages brain infiltrates and identify new metabolic targets for therapeutic approaches aimed at reducing smoldering neuroinflammation.


Assuntos
Encéfalo , Movimento Celular/imunologia , Macrófagos , Microglia , Doenças Neuroinflamatórias , Animais , Encéfalo/imunologia , Encéfalo/metabolismo , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Microglia/imunologia , Microglia/metabolismo , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/metabolismo
8.
PLoS Biol ; 19(4): e3001166, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33826607

RESUMO

Neural stem cell (NSC) transplantation induces recovery in animal models of central nervous system (CNS) diseases. Although the replacement of lost endogenous cells was originally proposed as the primary healing mechanism of NSC grafts, it is now clear that transplanted NSCs operate via multiple mechanisms, including the horizontal exchange of therapeutic cargoes to host cells via extracellular vesicles (EVs). EVs are membrane particles trafficking nucleic acids, proteins, metabolites and metabolic enzymes, lipids, and entire organelles. However, the function and the contribution of these cargoes to the broad therapeutic effects of NSCs are yet to be fully understood. Mitochondrial dysfunction is an established feature of several inflammatory and degenerative CNS disorders, most of which are potentially treatable with exogenous stem cell therapeutics. Herein, we investigated the hypothesis that NSCs release and traffic functional mitochondria via EVs to restore mitochondrial function in target cells. Untargeted proteomics revealed a significant enrichment of mitochondrial proteins spontaneously released by NSCs in EVs. Morphological and functional analyses confirmed the presence of ultrastructurally intact mitochondria within EVs with conserved membrane potential and respiration. We found that the transfer of these mitochondria from EVs to mtDNA-deficient L929 Rho0 cells rescued mitochondrial function and increased Rho0 cell survival. Furthermore, the incorporation of mitochondria from EVs into inflammatory mononuclear phagocytes restored normal mitochondrial dynamics and cellular metabolism and reduced the expression of pro-inflammatory markers in target cells. When transplanted in an animal model of multiple sclerosis, exogenous NSCs actively transferred mitochondria to mononuclear phagocytes and induced a significant amelioration of clinical deficits. Our data provide the first evidence that NSCs deliver functional mitochondria to target cells via EVs, paving the way for the development of novel (a)cellular approaches aimed at restoring mitochondrial dysfunction not only in multiple sclerosis, but also in degenerative neurological diseases.


Assuntos
Vesículas Extracelulares/metabolismo , Mitocôndrias/metabolismo , Células-Tronco Neurais/metabolismo , Animais , Transporte Biológico , Células Cultivadas , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células-Tronco Neurais/ultraestrutura
9.
Trends Immunol ; 42(1): 45-58, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33279412

RESUMO

The rapidly evolving area of immunometabolism has shed new light on the fundamental properties of products and intermediates of cellular metabolism (metabolites), highlighting their key signaling roles in cell-to-cell communication. Recent evidence identifies the succinate-succinate receptor 1 (SUCNR1) axis as an essential regulator of tissue homeostasis. Succinate signaling via SUCNR1 guides divergent responses in immune cells, which are tissue and context dependent. Herein, we explore the main cellular pathways regulated by the succinate-SUCNR1 axis and focus on the biology of SUCNR1 and its roles influencing the function of myeloid cells. Hence, we identify new therapeutic targets and putative therapeutic approaches aimed at resolving detrimental myeloid cell responses in tissues, including those occurring in the persistently inflamed central nervous system (CNS).


Assuntos
Inflamação , Células Mieloides , Receptores Acoplados a Proteínas G , Animais , Humanos , Inflamação/imunologia , Inflamação/patologia , Células Mieloides/imunologia , Células Mieloides/patologia , Receptores Acoplados a Proteínas G/imunologia , Transdução de Sinais
10.
Front Cell Neurosci ; 14: 590960, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33250716

RESUMO

Increasing evidence foresees the secretome of neural stem cells (NSCs) to confer superimposable beneficial properties as exogenous NSC transplants in experimental treatments of traumas and diseases of the central nervous system (CNS). Naturally produced secretome biologics include membrane-free signaling molecules and extracellular membrane vesicles (EVs) capable of regulating broad functional responses. The development of high-throughput screening pipelines for the identification and validation of NSC secretome targets is still in early development. Encouraging results from pre-clinical animal models of disease have highlighted secretome-based (acellular) therapeutics as providing significant improvements in biochemical and behavioral measurements. Most of these responses are being hypothesized to be the result of modulating and promoting the restoration of key inflammatory and regenerative programs in the CNS. Here, we will review the most recent findings regarding the identification of NSC-secreted factors capable of modulating the immune response to promote the regeneration of the CNS in animal models of CNS trauma and inflammatory disease and discuss the increased interest to refine the pro-regenerative features of the NSC secretome into a clinically available therapy in the emerging field of Regenerative Neuroimmunology.

11.
Front Aging Neurosci ; 12: 247, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32848716

RESUMO

The adult central nervous system (CNS) contains resident stem cells within specific niches that maintain a self-renewal and proliferative capacity to generate new neurons, astrocytes, and oligodendrocytes throughout adulthood. Physiological aging is associated with a progressive loss of function and a decline in the self-renewal and regenerative capacities of CNS stem cells. Also, the biggest risk factor for neurodegenerative diseases is age, and current in vivo and in vitro models of neurodegenerative diseases rarely consider this. Therefore, combining both aging research and appropriate interrogation of animal disease models towards the understanding of the disease and age-related stem cell failure is imperative to the discovery of new therapies. This review article will highlight the main intrinsic and extrinsic regulators of neural stem cell (NSC) aging and discuss how these factors impact normal homeostatic functions within the adult brain. We will consider established in vivo animal and in vitro human disease model systems, and then discuss the current and future trajectories of novel senotherapeutics that target aging NSCs to ameliorate brain disease.

12.
Sci Rep ; 10(1): 828, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964978

RESUMO

The aging brain is associated with significant changes in physiology that alter the tissue microenvironment of the central nervous system (CNS). In the aged CNS, increased demyelination has been associated with astrocyte hypertrophy and aging has been implicated as a basis for these pathological changes. Aging tissues accumulate chronic cellular stress, which can lead to the development of a pro-inflammatory phenotype that can be associated with cellular senescence. Herein, we provide evidence that astrocytes aged in culture develop a spontaneous pro-inflammatory and senescence-like phenotype. We found that extracellular vesicles (EVs) from young astrocyte were sufficient to convey support for oligodendrocyte differentiation while this support was lost by EVs from aged astrocytes. Importantly, the negative influence of culture age on astrocytes, and their cognate EVs, could be countered by treatment with rapamycin. Comparative proteomic analysis of EVs from young and aged astrocytes revealed peptide repertoires unique to each age. Taken together, these findings provide new information on the contribution of EVs as potent mediators by which astrocytes can extert changing influence in either the disease or aged brain.


Assuntos
Envelhecimento/patologia , Astrócitos/citologia , Astrócitos/fisiologia , Encéfalo/citologia , Encéfalo/patologia , Diferenciação Celular , Senescência Celular , Vesículas Extracelulares/fisiologia , Oligodendroglia/fisiologia , Animais , Células Cultivadas , Camundongos , Proteômica
13.
Neurochem Res ; 45(3): 694-707, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31900795

RESUMO

The aging brain is associated with significant pathophysiological changes reflected in changes in astrocyte function. In this study, we hypothesized that the response of astrocytes to mechanical and inflammatory stimulation would differ with long-term culture. We report that naïve short-term cultured (young) and long-term cultured astrocytes (aged) exhibit similar recovery to a scratch wound assay. However, in response to IL-1ß young astrocytes have an arrested recovery which is not observed in IL-1ß treated aged astrocytes. We had recently reported that astrocytes release extracellular vesicles (EVs) in response to IL-1ß treatment. Given the disparate phenotypes between young and aged astrocytes, we next examined whether the EVs released from astrocytes reflected the differences in cellular responses to scratch and IL-1B treatment. Young cultures challenged with EVs collected from IL-1ß treated cells exhibited a robust inhibition of wound recovery when compared to astrocytes treated with EVs collected from IL-1ß treated aged astrocyte cultures. Heterochronic experiments also determined that the effect of IL-1ß on astrocyte scratch wound recovery could be recapitulated by EVs alone. Taken together, these findings provide new information on how senescence alters the functional response and how EVs from astrocytes may elicit changes in glial responses which may have relevance to understanding neurological diseases.


Assuntos
Astrócitos/efeitos dos fármacos , Senescência Celular , Vesículas Extracelulares/efeitos dos fármacos , Interleucina-1beta/farmacologia , Animais , Astrócitos/fisiologia , Técnicas de Cultura de Células , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais
14.
Immunity ; 52(1): 167-182.e7, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31883839

RESUMO

Multiple sclerosis (MS) is a demyelinating, autoimmune disease of the central nervous system. While work has focused on myelin and axon loss in MS, less is known about mechanisms underlying synaptic changes. Using postmortem human MS tissue, a preclinical nonhuman primate model of MS, and two rodent models of demyelinating disease, we investigated synapse changes in the visual system. Similar to other neurodegenerative diseases, microglial synaptic engulfment and profound synapse loss were observed. In mice, synapse loss occurred independently of local demyelination and neuronal degeneration but coincided with gliosis and increased complement component C3, but not C1q, at synapses. Viral overexpression of the complement inhibitor Crry at C3-bound synapses decreased microglial engulfment of synapses and protected visual function. These results indicate that microglia eliminate synapses through the alternative complement cascade in demyelinating disease and identify a strategy to prevent synapse loss that may be broadly applicable to other neurodegenerative diseases. VIDEO ABSTRACT.


Assuntos
Complemento C3/imunologia , Encefalomielite Autoimune Experimental/patologia , Microglia/patologia , Esclerose Múltipla/patologia , Sinapses/patologia , Tálamo/patologia , Idoso , Idoso de 80 Anos ou mais , Animais , Callithrix , Linhagem Celular Tumoral , Complemento C3/antagonistas & inibidores , Modelos Animais de Doenças , Feminino , Gliose/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Receptores de Complemento 3b/metabolismo
15.
Brain Res ; 1729: 146615, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31863730

RESUMO

Compelling evidence from experimental animal disease models and early-phase clinical trials identifies the transplantation of neural progenitor/stem cells (NSCs) as a viable path towards the development of clinically applicable exogenous stem cell therapies. Building from current advances in the field of NSC biology and following the positive outcomes of NSC transplantation studies, the contemporary view is that transplanted NSCs act as local 'factories' capable of producing and secreting a wide array of immune and neurotrophic factors. This has launched a 'stem cell race' to identify the mechanisms behind stem-cell mediated repair in what has been labeled the paracrine hypothesis. This hypothesis proposes that NSC grafts act as a natural source of potent biologics capable of modulating and promoting the restoration of several key functions in the central nervous system (CNS) tissue following acute or chronic tissue damage. Investigators have been inspired to examine novel ways to harness and utilize the pro-regenerative properties of NSC therapies as an alternative approach to a more classical (small molecule based) treatment of CNS diseases. In this review, we will discuss the most recent findings of human NSC (hNSCs) transplants in experimental animal models of CNS diseases that identify of hNSC-secreted factors, including those trafficked within extracellular membrane vesicles (EVs), and the outcomes of recent clinical trials utilizing hNSC therapeutics in CNS diseases.


Assuntos
Doenças do Sistema Nervoso Central/terapia , Células-Tronco Neurais/transplante , Transplante de Células-Tronco/métodos , Animais , Humanos , Células-Tronco Neurais/metabolismo
16.
Proc Natl Acad Sci U S A ; 116(21): 10488-10493, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31068461

RESUMO

Extracellular vesicles (EVs) are emerging as potent mediators of intercellular communication with roles in inflammation and disease. In this study, we examined the role of EVs from blood plasma (pEVs) in an experimental autoimmune encephalomyelitis mouse model of central nervous system demyelination. We determined that pEVs induced a spontaneous relapsing-remitting disease phenotype in MOG35-55-immunized C57BL/6 mice. This modified disease phenotype was found to be driven by CD8+ T cells and required fibrinogen in pEVs. Analysis of pEVs from relapsing-remitting multiple sclerosis patients also identified fibrinogen as a significant portion of pEV cargo. Together, these data suggest that fibrinogen in pEVs contributes to the perpetuation of neuroinflammation and relapses in disease.


Assuntos
Linfócitos T CD8-Positivos/fisiologia , Encefalomielite Autoimune Experimental/imunologia , Vesículas Extracelulares/metabolismo , Fibrinogênio/metabolismo , Animais , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla , Recidiva
17.
Proc Natl Acad Sci U S A ; 116(18): 9030-9039, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-30910981

RESUMO

Cellular senescence is a form of adaptive cellular physiology associated with aging. Cellular senescence causes a proinflammatory cellular phenotype that impairs tissue regeneration, has been linked to stress, and is implicated in several human neurodegenerative diseases. We had previously determined that neural progenitor cells (NPCs) derived from induced pluripotent stem cell (iPSC) lines from patients with primary progressive multiple sclerosis (PPMS) failed to promote oligodendrocyte progenitor cell (OPC) maturation, whereas NPCs from age-matched control cell lines did so efficiently. Herein, we report that expression of hallmarks of cellular senescence were identified in SOX2+ progenitor cells within white matter lesions of human progressive MS (PMS) autopsy brain tissues and iPS-derived NPCs from patients with PPMS. Expression of cellular senescence genes in PPMS NPCs was found to be reversible by treatment with rapamycin, which then enhanced PPMS NPC support for oligodendrocyte (OL) differentiation. A proteomic analysis of the PPMS NPC secretome identified high-mobility group box-1 (HMGB1), which was found to be a senescence-associated inhibitor of OL differentiation. Transcriptome analysis of OPCs revealed that senescent NPCs induced expression of epigenetic regulators mediated by extracellular HMGB1. Lastly, we determined that progenitor cells are a source of elevated HMGB1 in human white matter lesions. Based on these data, we conclude that cellular senescence contributes to altered progenitor cell functions in demyelinated lesions in MS. Moreover, these data implicate cellular aging and senescence as a process that contributes to remyelination failure in PMS, which may impact how this disease is modeled and inform development of future myelin regeneration strategies.


Assuntos
Senescência Celular/fisiologia , Esclerose Múltipla Crônica Progressiva/fisiopatologia , Células-Tronco Neurais/fisiologia , Animais , Axônios/patologia , Diferenciação Celular/fisiologia , Células Cultivadas , Humanos , Células-Tronco Pluripotentes Induzidas , Esclerose Múltipla/fisiopatologia , Bainha de Mielina/metabolismo , Regeneração Nervosa/fisiologia , Neurônios/metabolismo , Proteômica/métodos , Ratos , Remielinização/fisiologia
18.
Mol Neurobiol ; 56(5): 3380-3392, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30121936

RESUMO

The extracellular protein tissue inhibitor of metalloproteinase (TIMP)-1 is both a matrix metalloproteinase (MMP) inhibitor and a trophic factor. Mice lacking TIMP-1 exhibit delayed central nervous system myelination during postnatal development and impaired remyelination following immune-mediated injury in adulthood. We have previously determined that the trophic action of TIMP-1 on oligodendrocyte progenitor cells (OPCs) to mature into oligodendrocytes is independent of its MMP inhibitory function. However, the mechanism by which TIMP-1 promotes OPC differentiation is not known. To address this gap in our understanding, herein, we report that TIMP-1 signals via a CD63/ß1-integrin receptor complex to activate Akt (protein kinase B) to promote ß-catenin signaling in OPCs. The regulation of ß-catenin by TIMP-1 to promote OPC differentiation was counteracted, but not abrogated, by canonical signaling evoked by Wnt7a. These data provide a previously uncharacterized trophic action of TIMP-1 to regulate oligodendrocyte maturation via a CD63/ß1-integrin/Akt pathway mechanism. These findings contribute to our emerging understanding on the role of TIMP-1 as a growth factor expressed to promote CNS myelination during development and induced in the adult to promote myelin repair.


Assuntos
Diferenciação Celular , Oligodendroglia/citologia , Oligodendroglia/enzimologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Tetraspanina 30/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Animais , Células Cultivadas , Ativação Enzimática , Integrina beta1/metabolismo , Domínios Proteicos , Ratos Sprague-Dawley , Inibidor Tecidual de Metaloproteinase-1/química , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
19.
Front Neurosci ; 11: 335, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28663721

RESUMO

Astrocytes are the most abundant glial cell type in the central nervous system (CNS) and are known to fulfill critical homeostatic functions. Dysfunction of activated astrocytes is also known to participate in the development of several neurological diseases. Astrocytes can be uniquely identified by expression of the intermediate filament protein glial acidic fibrillary protein (GFAP). Herein, we report on the development of a rigorous and sensitive methodology to identify GFAP+ exosomes in primary culture using flow cytometry. We then demonstrate that activated astrocytes release increased amounts of exosomes in response to treatment with interleukin-1ß. Using this methodology, we report the identification of GFAP+ exosomes in blood and then use a mouse model of inflammatory demyelination, experimental autoimmune encephalomyelitis (EAE), to examine whether the abundance of GFAP+ exosomes in blood circulation changes during clinical illness. We find a detectable increase in the presence of GFAP+ exosomes in EAE mice when compared with non-EAE, control mice. Our data provide a novel perspective on the presence of GFAP in blood as it identifies exosomes as potential astrocyte-derived signals within blood. These data are complementary to previous clinical studies that reported elevated GFAP protein in blood samples from multiple sclerosis (MS) patients during a clinical relapse. These data also reveal the existence of a potential systemic role for astrocyte-derived exosomes in CNS conditions involving inflammation such as multiple sclerosis.

20.
Exp Neurol ; 288: 114-121, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27865736

RESUMO

Primary progressive multiple sclerosis (PPMS) is a chronic demyelinating disease of the central nervous system (CNS) currently lacking any effective treatment. Promoting endogenous brain repair offers a potential strategy to halt and possibly restore neurologic function in PPMS. To understand how the microenvironment within white matter lesions plays a role in repair we have focused on neural progenitor cells (NPCs) since these are found in lesions in PPMS and have been found to influence oligodendrocyte progenitor cell maturation (OPCs). To better understand the cellular nature of NPCs in PPMS we developed iPS cells from blood samples of PPMS patients and age matched non-disease spouse or blood relative controls. Using these iPS cell lines we determined that the NPCs from PPMS cases provided no neuroprotection against active CNS demyelination compared to NPCs from control iPS lines which were capable of completely preventing injury. Conditioned media (CM) from PPMS NPCs provides no protection to OPCs and prevents maturation of OPCs into oligodendrocytes in vitro. We also found that CM from PPMS iPS NPCs elicited patient-specific differences in the response to compounds that should foster oligodendrocyte (OL) maturation. Together, these data establish a new model for understanding the nature of myelination defects in PPMS which may lead to novel targeted approaches for preventing demyelination in these patients.


Assuntos
Células-Tronco Pluripotentes Induzidas/patologia , Esclerose Múltipla Crônica Progressiva/patologia , Bainha de Mielina/patologia , Idoso , Animais , Apoptose/efeitos dos fármacos , Axônios/patologia , Axônios/ultraestrutura , Diferenciação Celular/efeitos dos fármacos , Clemastina/farmacologia , Clemastina/uso terapêutico , Meios de Cultivo Condicionados/farmacologia , Cuprizona/toxicidade , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/química , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/ultraestrutura , Masculino , Camundongos Endogâmicos C57BL , Miconazol/farmacologia , Miconazol/uso terapêutico , Pessoa de Meia-Idade , Inibidores da Monoaminoxidase/toxicidade , Esclerose Múltipla Crônica Progressiva/induzido quimicamente , Proteína Básica da Mielina/metabolismo , Bainha de Mielina/ultraestrutura , Proteínas do Tecido Nervoso/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/patologia , Oligodendroglia/ultraestrutura
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